Abstract Pneumonia remains the #1 killer of children in the world and is a leading cause of morbidity and mortality in children in the US and the #8 cause of mortality in adults. Our laboratory has made seminal insights in mechanisms underlying host defense against extracelluar pathogens ? particularly in the area of type 17 cytokines ?IL-17 and IL-22. We have identified novel pathways that regulate host immunity against Pneumocystis including CD4+ T-cell intrinsic IL21R expression and STAT3 activation. We will determine how CD4+ T-cell STAT3 regulates host resistance and test the specific roles of IL-22, GM-CSF and CD209 isoforms. Furthermore we will examine the role of IL-22RA2 in regulating the availability of free IL-22 in the lung and study the contributions of tissue resident memory cells in host defense against bacterial pneumonia. The research prosed under this R35 will shed new light on pulmonary host defenses that can be exploited to reduce the global burden of pneumonia mortality and morbidity.